Amino-9,10-dihydro-9,10-dioxo-2-anthroic acids

ABSTRACT

Anthraquinone derivatives of the general formula I :   and pharmaceutically acceptable salts and esters thereof, WHEREIN R1 represents a halogen atom, a hydroxyl group or a group -OR2, (in which R2 may be a lower alkyl group containing from 1 to 6 carbon atoms optionally substituted by a hydroxy group, an aryl group, an aryloxy group, an alkoxy group or a dialkylamino group) or a group -NR3R4, (in which R3 and R4 which may be the same or different, represent a hydrogen atom, a lower alkyl group containing from 1 to 6 carbon atoms, optionally substituted by a hydroxy group, or R3 and R4 together with the nitrogen atom may form a ring which may optionally be substituted with another heteroatom); with the proviso that when R1 is a halogen atom or a methoxy group mixtures of positional isomers produced by existing chemical processes are excluded.

United States Patent [1 1 Oxford et al.

1 1 AMINO-9,10-DIHYDRO-9J0-DIOXO-2- ANTHROIC ACIDS [75} Inventors: Alexander William Oxford; Geoffrey Edward Gymer. both of London, England [73] Assignee: Allen & l-lansburys Limited,

- London, England [22] Filed: July 19, 1971 [21] Appl. No.: 164,093

[30] Foreign Application Priority Data Aug. 5, 1970 United Kingdom 37724/70 Aug. 5, 1970 United Kingdom 37725/70 [521 US. Cl ..260/247.2 R,260/247.2 B,

[511 int. Cl.. C07d 29/24, C07d 51/70, C07d 87/36 5 Field of Search 260/376, 268 TR. 247.2 B, 260/2472 R, 293.62, 272

[56] References Cited UNlTED STATES PATENTS 1,915,334 6/1933 Salzberg et al. 260/243 2,075,359 3/1937 Salzberg et al. 260/293.51 2,195.974 4/1940 Reppe et a1 260/376 2,362,614 11/1944 Calva 424/325 2.852.534 9/1958 Klinsberg 260/376 3,089,879 5/1963 Serres, Jr. et al 260/376 OTHER PUBLlCATlONS .N. S. Dokunikhin et al., Chemical Abstracts, Vol. 57,

p. 8516 g, (1961). N. S. Dokunikhin et al., Chemical Abstracts, Vol. 64, pages 15797-15798, (1964).

[ 51 Mar. 25, 1975 Primary Iiruminvr-Alton D. Rollins .-ls.ri.rtunt I:'.\'uminw'-.Josc l'ovar 1 .41101'110), .-1gcn!, or Firm liacon & llltlllltlS n I 157] ABS'I RACl Anthraquinone-derivatives of the general formula 1 6 carbon atoms, optionally substituted by a hydroxy group, or R and R together with the nitrogen atom may form a ring which may optionally be substituted with another heteroatom); with the proviso that when R is a halogen atom or a methoxy group mixtures of positional isomers produced by existing chemical pro cesses are excluded.

12 Claims, N0 Drawings AMINO-9,10-DIHYDRO-9,IO-DIOXO-Z-ANTHROIC AC IDS This invention relates to novel anthraquinone derivatives, to processes for the preparation thereof and to compositions containing such derivatives.

We have found that certain novel anthraquinone derivatives have useful immunological activities and in particular inhibit the release of spasmogens that normally occurs when a reaginic antibody combines with an antigen.

The present invention accordingly provides anthraquinone derivatives of general formula I:

COOH

wherein R, represents a halogen atom, a hydroxyl group or a group OR in which R, may be a lower alkyl group containing from 1 toa6 carbon atoms, preferably l to 4 carbon atoms optionally substituted by a hydroxy group, an aryl group, an aryloxy group, an alkoxy group or a dialkylamino group. R, may also represent the group NR,,R,, in which R,, and R,, which may be the same or different, represent a hydrogen atom or a lower alkyl group containing from l to 6 carbon atoms, prefc|'abl l to 4 carbon atoms optionally substituted by a hydroxy group, or R and R together with the nitrogen atom may form a ring which may optionally be substituted by another heteroatom, e.g. piperidino, morpholino or N-methylpiperazino, with the proviso that when R, is a halogen atom or a methoxy group the invention does not extend to mixtures of positional isomers produced by existing chemical processes.

The production ofcompounds in which R, represents a halogen atom or a methoxy group has been described but by a process which we have ascertained leads to a mixture of two isomers. The present invention provides inter alia as described below a process which results in the production ofsclccted isomers in substantially pure form. It is believed that the compounds in which R, represents a halogen atom or a methoxy group are novel when in the form of substantially pure isomers.

The invention also includes salts, for example those with alkali metals such as sodium, with organic bases such as dimethylaminoethanol, and with mineral and organic acids, as well as esters of the carboxylic acids, such as simple alkyl esters and those described in the Examples.

The compounds according to the invention have the property of inhibiting the release of spasmogen mediators in the antigen-antibody reaction. Thus, for example, 9.l0-dihydro-7-(2-hydroxyethoxy)-9,lO-dioxo-2- anthoic acid has been found to be about times as active as disodium cromoglycate in inhibiting the passive cutaneous anaphylaxis (PCA) reaction in the rat using the nematode Nimmslrongylis brasiliensis as the antigen (Ogilvic, Brit. J. lmmunol., I967, 12 (2) |l3l3l The use of the compounds is therefore indicated in the treatment of any condition in which an extrinsic antigen combination with antibody is primarily responsible, as, for example, in allergic asthma, hay fever, urticaria, eczema, or atopic dermatitis.

Preferred compounds according to the invention are those the preparation of which is described in the Examples.

The invention further provides pharmaceutical compositions comprising a compound according to the invention in association with a pharmaceutically acceptable carrier.

The compounds according to the invention. may be formulated for use as pharmaceutical compositions in the conventional manner with the aid of carriers or excipients and formulatory agents as required and with or without supplementary medicinal agents. Oral administration is most convenient in the form of tablets which may be coated,-pastes, aqueous or oily suspensions, solutions, emulsions, or capsules. Carriers include inert diluents such as calcium carbonate and/or disintegrating agents such as alginic acid or starch. Magnesium stearate may be used as a lubricating agent and flavouring or sweetening agents include sucrose, dextrose, glucose, gylcerol etc. For emulsions suspending agents such as sodium carboxymethyl cellulose may be used, Injections may be formulated with the aid of physiologically acceptable carriers and agents as solutions, or as dry products for reconstitution before use. For administration by inhalation the compositions according to the invention may conveniently be in the form of an aerosol spray presentation including both pressurised cans and nebulisers. The dosage at which the active ingredient is administered may vary within a wide range. A suitable oral dosage range is generally from 5 to 1500 mg. The pharmaceutical compositions may, with advantage, be formulated to provide a dose within this range either as a single unit or a number of units. In the use of an aerosol the dosage unit may be determined by providing a metering valve in the aerosol pack so that it delivers a metered amount on use. Such a metered amount may be of the order of ll() mg. The compositions may be presented in combination with a bronchodilator as required.

The compounds ofthe present invention may be prepared by a method which involves oxidation of an anthrone carboxylic acid of the formula II:

pared by reduction of the substituted benzophenone lll by treatment for example with elemental phosphorus and hydriodic acid in the presence of acetic acid.

' co a Y halogen 3 4 The reaction lVV is an example ofthis. The prepa- Z. Z. Moiseeva and S. N. Burenko. Zhur Obshchci. compoundsflccording mention 14111111. 31. 3985 1961; c. A. 57 8516.) incorporated therefore be illustrated for example with reference to the production of the 7-fluoro compound Vll as follows: zophenone diacid in fuming sulphuric acid.

the cyclisation of the appropriate halo-substituted ben- PZHI' 9 AcOH F coon v IV CrO XcQI-I COOH' VII 0 COOH SO 7 3 Y 00H 00H I I v I 130-1491) Y Chloro or fluoro.

This is an unambiguous synthesis which does not pro- However, under these conditions we found that vide for the possibility ofisomerism and makes possible 4-fluorobenzophenone-2,4- and 2,, 5 -dicarboxylic the production ofpure isomers which has not hitherto acids cyclised to the same product (m.p. 297300), been achieved. which is a mixture of the 6- and 7- fluoroanthraquinones. It appears to us that the isomers The previous proposed synthesis (N.S. Dokunikhin, are probably formed by a rearrangement analogous to B. V. Salov and A. S. Glagoleva, Zhur ObshcheiKhim, the Hayashi rearrangement of certain o-benzoyl- 34 (3). 995. 1964; C. A. 15797. N. S. Dokunikhin. benzoic acids,

COOH

3,873,538 6 and that a spiro intermediate is involved in this type of standard methods of chemistry described in the Examreaction. ples.

0, COOH coon coon . coon Similar behaviour was observed with the correspond- 'It is understood that the conversion of any of the ing 4-chloro-benz0phenone diacids and both 2-chlorogroups (R, Hal) into the groups (R OR benzophenone-Z, 4 and 2',5-dicarboxylic acids cy- NR R can be effected at any convenient time in the clise to mixtures of the 5- and 8-chloro-9,l0-dihydroabove process. 9,10-dioxo-2-anthroic acids. The following Examples illustrate the invention:

By the process of the present invention as described we have been able to obtain the isomers separately. EXAMPLE 1 The m.p. values observed by us and those reported in the literature are set out below.

The infra-red spectra of the reported compounds 2-(p-Fluorobenzoyl)isophthalic acid) (2.5 g.),amorhave absorption bands of both pure isomers which is a phous phosphorus (2.0 g.), hydriodic acid (1.5 ml.;

2-(p-Fluorobenzyl)isophthalic acid further indication that the reported compounds are 64-68%),water(l ml.) and glacial acetic acid( ml.) mixtures. were boiled under reflux for 4 hours. Phosphorus was TABLE OhSLrYCtl 320 354-3535 305-307 3|3-315 323-324 300-302 Reported 3024-310 3335-335 336-339 323-324 282-284 292-294 The compounds of general formula I wherein R, repfiltered off and the filtrate was decolourised with soresents a halogen atom, particularly a fluorine atom, as dium metabisulphite and diluted with water. The diacid well as being intrinsically active in the PCA test are was collected, drled and recry lli frOm aqueous valuable intermediates for the preparation of the comethanol, p 2340-3370 g)- pounds of the invention where R is hydroxyl or the By a similar procedure 2-( l n y l p groups OR or NR R thalic acid gave 2-(4-fluorobenzyl)terephthahc acid,

The haloanthraquinone is treated for example with mp 293297; 2-(oh 0r 0y l p acid an amine R R NH or an alkoxide R- OM where M is an gave 2-(p-chlorobenzyl)terephthalic acid, mp

alkali-metal, for example such as sodium. 285287; 2-(p-chlorobenzoyl)isophthalic acid gave This reaction is best carried out in a solvent, for ex- 2-(p-chlorobenzyl)isophthalic acid, mp 225229; 2-

ample dimethylformamide, at an elevated temperature (o-chlorobenzoyl)terephthalic acid gave 2-(0- (50lOOC). Compounds according to the invention in chlorobenzyl)terephthalic acid, mp 3 l 6320.

which R is OH may be prepared from compounds in which R is OR- by standard reactions such as heat- EXAMPLE 2 ing under reflux with hydrogen bromide in acetic acid. 7-Fluoro-9,l()-dihydro-9,lU-dioxo-Z-anthroic acid Esters of the carboxyl group may be prepared by 2-(p-Fluorobcnzyl)isophthalic acid (1.0 g.) in conacid, mp 354-355.5; Z-(p-chlorobenzyl)isophthalic acid gave 7-chloro-9,l0-dihydro-9,l0-dioxo-2-anthroic acid. mp 305-307; Z-(o-chIorobenzyl)terephthalic acid gave 8-chloro-9,l0-dihydro-9,l0-dioxo-2-anthroic acid, mp 3l33.l5; and 2-(4-fluorobenzyl)terephthalic acid gave 6-lluoro-9,l0-dihydro-9,l0-dioxo'2- anthroic acid, mp 32l324.

EXAMPLE 3 9,lO-Dihydn)-8-methoxy-9,l0-dioxo-2-anthroic acid 8-Chloro-9,l0-dihydro-9,lO-dioxoQ-anthroic acid (0.8 g.) in dimethyllormamide (100 ml.) containing a lN solution of sodium in dry methanol (ll ml.) was stirred at 90 for 3 hours. The mixture was cooled, poured into 2N hydrochloric acid (150 ml.) and extracted with ethyl acetate. The extracts were evaporated to give a yellow solid which was crystallised from acetic acid, 0.4 g., mp 3053l0.

EXAMPLE 4 9,l-Dihydro 7-methoxy-9,l0-dioxo-2-anthroic acid and dimethylaminoethanol salt 7-Fluoro-9,l0-dihydro-9,l0-dioxo-2anthroic acid (I g.) in dimcthyll'ormamide (100 ml.) containing a 0.9N solution ol'sodium methoxidc in dry methanol l 3 ml.) was stirred at 90 for 30 minutes. It was cooled, poured into 2N hydrochloric acid. and the precipitated solid was filtered oft" and crystallised from galcial acetic acid to give a yellow solid (0.95 g.) mp 272.5275.5. The acid (0.9 g) was dissolved in warm dimethylaminoethanol (10 ml.), cooled and diluted with ether togive the Z-dimethylaminoethanol salt as a yellow solid mp l76l79.

In a similar manner were prepared: 9,l0-dihydro-6- methoxy-9,l0-dioxo-2-anthroic acid, mp 31 l.5-314. Z-Dimethylaminoethanol salt mp 237239. 9,10- Dihydro-7-propoxy-9,l0-dioxo-2-anthroic acid, mp 267-270.

EXAMPLE 5 9, l O-Dihydro-7-( 2-hydroxyethoxy)-9, l 0-dioxo-2- anthroic acid Sodium (0.5 g) was dissolved in ethane-l,2-diol ml.) and added to a solution of 7-fluoro-9,l0-dihydro- 9,10-di0xo-2-anthroic acid (1 g.) in dimethylformamide (100 ml.). The mixture was heated at 100 for 1 hour, cooled, poured into 2N hydrochloric acid (150 (3-hydroxypropoxy)-9, l 0-dioxo-2-anthroic acid, mp 23l234.

9, l 0-Dihydro-7-( 2-methoxyethoxy)9, l0-dioxo-2- anthroic acid, mp 227-229.

7-(2-Dimethylaminoethoxy)-9,l0-dihydro9,l0- dioxo-2-anthroic acid, hydrochloride, mp 276-277.

9,10-Dihydro-7-(phenethyloxy)-9, lO-dioxo-2- anthroic acid mp 229.5-232.5.

9,l0-Dihydro-9,l0-dioxo-7-(Z-phenoxyethoxy)-2- anthroic acid, mp 224225.5.

'9,l0-Dihydro-6-(2-hydroxyethoxy)-9,l0-dioxo2 anthroic acid, mp 266-270. Z-Dimethylaminoethanol salt, mp 2092l 1.

9,l0-Dihydro-6-(3-hydroxypropoxy)-9,l0-dioxo-2- anthroic acid, mp 2l0-2l4. Z-Dimethylaminoethanol salt, mp l6l3.

EXAMPLE 6 9. l 0-Dihydro7-morpholino-9. l (l-dioxo-Z-anthroic acid 7-Fluoro-9,l0-dihydro-9.l0-dioxo-Z-anthroic acid l g.), morpholine (2 g.) in dimethyll'ormamide ml.) were heated at 100 for 2 hours. The mixture was cooled and poured into 2N hydrochloric acid ml.). The precipitated red solid was filtered off (0.9 g.) mp 31l-314.

In a similar manner were prepared: 9,l0-Dihydro-7- piperidino-9,l0-dioxo-2-anthroic acid, mp 296297. Z-Dimethylaminoethanol salt, mp 280.

9,l0-Dihydro-6-morpholino-9,l0-dioxo-2-anthroic acid, mp 3l23l5.

9,l0-Dihydro-7-(4-methyl-l-piperazinyl)9,l0- dioxo-Z-anthroic acid, mp 27 l(dec.). Hydrochloride, mp 339 C (dec.).

9,l0-Dihydro-7-(2.6-dimethylmorpholino)-9.l()- dioxo-2-anthroic acid. mp 323325.

9, l 0-Dihydro-7-dimcthylamino-9. l O-dioxo-Z- anthroic acid, mp 355357.

9, l 0-Dihydro-6-piperidino-9, l0-dioxo-2-anthroic acid, mp 284287.

EXAMPLE 7 9,10-Dihydro-5-morpholino-9,l0-dioxo-2-anthroic acid A solution of 5-chloro-9,lO-dihydro-9,lO-dioxo-2- anthroic acid (0.4 g.) in morpholine (15 ml.) was heated at 100 for 4 hours. Solid separated during this period. The mixture was diluted with water and aciditied; the required acid separated as a red solid (0.4 g). Recrystallisation from dimethylformamide and acetic acid gave a mauve solid, mp. 230232 (0.25 g).

In a similar manner w as preparedf 9,l0 Dihydro-7- [bis-(2-hydroxyethyl)amino]-9,lO-dioxo-Z-anthroic acid, mp 23924l.

EXAMPLE 8 9, l 0-Dihydro-7-( 4-methyl 1 -piperazinyl )-9, 1 O-dioxo- 2-anthroic acid, 2,2-dimethyl-1,3-dioxolanemethyl ester 9,l0-Dihydro-7-fluoro-9,10-dioxo-2-anthroyl chloride (1.5 g), 2,2-dimethyl-l,3-dioxolanemethanol (0.76 g.) (P. E. Verkade et al., Rec. trav. chim., 55 267 (1936)), triethylamine (0.66 g) in methylene chloride (60 ml.) was stirred at room temperature for 2% hours. The solvent was removed to give a solid which was washed well with water and crystallised from aqeuous ethanol to give 9,10-dihydro-7-fluoro-9,lO-dioxo-Z- anthroic acid, 2,2-dimethy1-l,3-dioxolanemethyl ester (1.6 g), mp. 127.5-129.5.

The above ester (1.5 g) and N-methylpiperazine (2.43 g) in N-methyl-2-pyrrolidone (150 ml.) was stirred at 100 for 35 minutes. The mixture was cooled. poured onto ice and the precipitated red solid filtered off and recrystallised twice from ethyl acetate to give the product (0.8 g), mp 164-l66.5.

In a similar manner was prepared: 9,10-Dihydro-7- morpho1ino-9,10-dioxo-2-anthroic acid, 2.2-dimethyl- 1,3-dioxolanemethyl ester, mp 187.5l88.5.

EXAMPLE 9 9,10-Dihydro-7-(4-methyl-1-piperazinyl)-9,lO-dioxol Z-anthroic acid, 2,3-dihydroxypropyl ester, hydrochloride 9.l-Dihydro-7-(4-methyl-l-piperaZinyl)-9,10- dioso-Z-anthroie acid, 2,2-dimethy1-1,3-dioxolane methyl ester (0.5 g.) in 2571 aqueous acetic acid (25 ml.) was heated at 100 for 3 hours. The solvent was removed in vacuo, the resulting red solid dissolved in ethyl acetate and the hydrochloride precipitated by the addition of ethyl acetate containing 10% of hydrogen chloride. The hydrochloride was crystallised twice from aqueous acetone to give the product (0.15 g) mp 258-259.

In a similar manner was prepared (omitting the addition of hydrochloric acid): 9,10-Dihydro-7- morpholino-9,l0-dioxo-2-anthroic acid, 2,3-dihydroxypropyl ester, mp 247249.5.

EXAMPLE l0 9.10-Dihydro-7-fluoro-9,l0-dioxo-2-anthroic acid, pivaloyloxymethyl ester and hydroxymethyl ester 9,10-Dihydro-7-fluoro-9,lO-dioxo-Z-anthroic acid (1.0 g.), chloromethylpivalate (1.11 g.) (M. Rasmussen et al., J. Amer. Chem. Soc., 89 5442 (1967), sodium hydride (0.178 g) (50% dispersion in oil) in N-methyl-2-pyrrolidone (100 ml.) was stirred at 100 for 50 minutes. It was cooled, poured onto ice and extracted with ethyl acetate. The extracts were concen-' trated to small volume, diluted with a little water and cooled. The precipitated solid was filtered off and crystallised from a mixture of chloroform and light petroleum (b.p. 60-80) to give the hydroxymethyl ester (04 g.). mp 228228.5 (with softening at 212). Evaporation of the mother liquors from this crystallisation afforded a second compound which was recrystal- 9.10-Dihydro-7-fluoro-9.1(l-dioxo-Z-anthroie acid. pivaloyloxymethyl ester (0.5 g). morpholine (0.7 g.) in N-methyl-2-pyrrolidone ml.) was stirred at for 1 hour. It was cooled. poured onto ice and the precipitated solid crystallised from a mixture o1- chloroform and light petroleum ether (hp. 6()-.\ 0) to give the ester (0.4 g.), mp -177.5.

In a similar manner were prepared: .l0-Dihydro-7- (4-methyl-l-piperazinyl)-9.lO-dioxo-Z-anthroie acid, pivaloyloxymethylester. hydrochloride. mp 350 \\'ith softening at 260270.

9, 10-Dihydro-7-(4-methyll -piperazinyl )-9, l 0- dioxo-Z-anthroic acid, hydroxymethyl ester, hydrochloride, mp 312 with decomposition.

The hydrochlorides were prepared by the procedure described in Example 9.

What is claimed is:

1. An anthraquinone of the formula:

wherein R and R are hydrogen, lower alkyl from 1 to 6 carbon atoms, hydroxyethyl or R and R together with the nitrogen atom, form a morpholino, piperidino, N-methylpiperazino or 2,6-dimethylmorpholino group; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 which is 9,10-Dihydro- 7-morpholino-9,10-dioxo-2-anthr0ic acid.

3. The compound of claim 1 which is 9,10-Dihydro- 7-piperidino-9,10-dioxo-2-anthroic acid.

4. The dimethylaminoethanol salt of the compound of claim 3.

5. The compound of claim 1 which is 9,10-Dihydro- 6-morpholino-9,10-dioxo-2-anthroic acid.

6. The compound of claim I which is 9,10-Dihydro- 7-(4-mcthyl-l-piperazinyl)-9,10-dioxo-2-anthroic acid. 7. The hydrochloride of the compound of claim 6.

8. The compound of claim 1 which is 9.10-Dihydro- 7-(2,6-dimethylmorpholino)-9,l0-dioxo2-anthroic lised from ethanol to give the pivaloyloxymethyl ester (0.7 g.), mp 113.5115.5.

EXAMPLE ll 9, l 0-Dihydro-7-morph0lino-9, l 0-dioxo-2-anthroic acid, pivaloyloxymethyl ester acid.

9. The compound-of claim 1 which is 9,10-Dihydro- 7-dimethy1amino-9,l0-dioxo-2-anthroic acid.

10. The compound of claim 1 which is'9,10-Dihydro- 6-piperidino9,l0-dioxo-2-anthroic acid.

11. The compound of claim 1 which is 9,10-Dihydro- 5-morpholino-9,l0-dioxo-2-anthroic acid.

12. The compound of claim 1 which is 9,10-Dihydro- 

1. AN ANTHRAQUINONE OF THE FORMULA:
 2. The compound of claim 1 which is 9,10-Dihydro-7-morpholino-9, 10-dioxo-2-anthroic acid.
 3. The compound of claim 1 which is 9,10-Dihydro-7-piperidino-9, 10-dioxo-2-anthroic acid.
 4. The dimethylaminoethanol salt of the compound of claim
 3. 5. The compound of claim 1 which is 9,10-Dihydro-6-morpholino-9, 10-dioxo-2-anthroic acid.
 6. The compound of claim 1 which is 9,10-Dihydro-7-(4-methyl-1-piperazinyl)-9,10-dioxo-2-anthroic acid.
 7. The hydrochloride of the compound of claim
 6. 8. The compound of claim 1 which is 9,10-Dihydro-7-(2,6-dimethylmorpholino)-9,10-dioxo-2-anthroic acid.
 9. The compound of claim 1 which is 9,10-Dihydro-7-dimethylamino-9,10-dioxo-2-anthroic acid.
 10. The compound of claim 1 which is 9,10-Dihydro-6-piperidino-9,10-dioxo-2-anthroic acid.
 11. The compound of claim 1 which is 9,10-Dihydro-5-morpholino-9,10-dioxo-2-anthroic acid.
 12. The compound of claim 1 which is 9,10-Dihydro-7-(bis-(2hydroxyethyl)amino)-9,10-dioxo-2-anthroic acid. 